Basic esters of mandelic acid and a process of making same



United States Patent BASIC ESTERS OF MANDELIC ACID AND A PROCESS OF MAKING SAME August Kottler and Gerhard Ohnacker, Biberach (Riss), Germany, assignors to Dr. Karl Thomae G.m.b. H., Biberach (Riss), Germany, a corporation of Germany No Drawing. Application March 15, 1957 Serial No. 646,195

Claims priority, application Germany August 5, 1954 6 Claims. (Cl. 260-3263) OH /R: JF-C O O-X -N R2 E R4 1 while their acid addition salts and their quaternary ammonium compound-s correspond to the following formula In said Formulas I and H,

E indicates the 2,5-endomethylene-M-cyclohexenyl radical or the 2,5-endomethylene-cyclohexyl radical;

R indicates hydrogen, an alkyl radical, preferably an alkyl radical with 1 to 6 carbon atoms or an alkoxy group, preferably an alkoxy group with 1 to 4 carbon atoms;

R; indicates hydrogen or an alkoxy group, preferably an alkoxy group with 1 to 2 carbon atoms;

R, and R indicate an alkyl radical, preferably an alkyl radical with 1 to 4 carbon atoms, and R and R together with the nitrogen atom to which they are attached may be a heterocyclic ring, preferably a pyrrolidine, piperidine or morpholine ring;

R indicates hydrogen or an alkyl or aralkyl radical, preferably an alkyl radical with 1 to carbon atoms;

X indicates a straight-chain or branched alkylene radical, preferably an alkylene radical with 1 to 4 carbon atoms;and

Y indicates the anion of an inorganic or organic acid.

Said new basic esters of the above-given general Formula I are produced according to the present invention by reacting an a-keto carboxylic acid or its esters ofthe following formula ice wherein R and R are the same substituents as indicated above while R indicates hydrogen or an alkyl radical, with an organo-metal compound of a 2,5-endomethylene compound of the following Formulas IVa and IVb a ra wherein Z indicates alkali metal or, preferably, the magnesium halogenide radical, and hydrolyzing the resulting reaction product.

The endocyclically-substituted mandelic acids obtained thereby and corresponding to the following formula OH All-C0011 R: E V

wherein R R and E are the same substituents as indicated above, are then reacted with amino alkyl halogenides of the following formula /Ra Hal-X-N R4 VI wherein R R and X are the same substituents as indicated above, while Hal is halogen, or endocyclicallysubstituted rnandelic acids corresponding to Formula V as given above or their metal salts, or respectively, their alkyl esters are reacted with amino alcohols of the following formula R4 VII wherein R R and X are also the same substituents as indicated above.

' Reaction of the organo-metal compounds of Formula IVa or lVb with a-keto carboxylic acids, or their esters of the above-given Formula III, is carried out under anhydrous conditions, preferably in the presence of an inert solvent, such as ether, benzene or tetrahydrofurane. Preferably, said reaction is effected at elevated temperature and more advantageously at the boiling temperature of the solvent employed. For instance, an especially advantageous mode of performing the reaction consists of first cooling the reaction mixture to a temperature between about 20 C. and about +5 C. and then completing the reaction by increasing the temperature, preferably to the boiling temperature of the solvent employed. The resulting reaction products are hydrolyzed, for instance by the addition of ice and hydrochloric acid.

Esters of endocyclically-substituted mandelic acids produced by said reaction can be saponified, if desired, to the corresponding free mandelic acids of the above-given Formula V. Saponification is eifected, for instance, by boiling with alkali hydroxide or alkali carbonate in an aqueous suspension of the ester or in the presence of a suitable water-soluble solvent, for instance in the presence of ethanol.

The reaction of endocyclically-substituted mantlelic acids of the above-given Formula V with amino alkylensues carried out in-the presence of an inert solvent, such as I isopropanol. Furthermore, said reaction is also advantageously efiected at elevated temperature, preferably at the boiling temperature of the solvent employed. Frequently it is of advantage to operate in the presence of a hydrogen halide-binding agent, for instance in the presence of an alkali alcoholate.

Direct esterification of endocyclically-substituted .mandelic acids of the above-given Formula V "with amino alcohols of the above-given Formula VII is carried out with or without esterification catalysts or by employing azeotropic methods to continuously remove the water formed by the esterification. Reaction of alkyl esters of endocyclically-substituted mandelic acids of Formula V with amino alcohols of Formula VII is preferably effected in the presence of a basic catalyst and advantageously in the presence of alkali metal or alkali metal alcoholate. Said condensation can be carried out in the presence or absence of solvents. Suitable solvents are, for example, tolueneor xylene. The reaction temperature may be as high as 150 C. The preferred temperature range is between about 110 C. and about 130 C. If required, esterification can be effected under reduced pressure.

The resulting basic esters can be converted, if desired, into their acid addition salts or their quaternary ammonium compounds, said salts and compounds corresponding to the above-given Formula II. For this purpose, the esters of Formula I are reacted, if required in the presence of solvents, with compounds of the following formula R Y VIII wherein R and Y are the same substituents as indicated above.

As solvents, there can be employed, for instance, ether, ethanol, acetone, acetic acid ethyl ester, benzene, and the like. Salt formation and quaternization can be effected at a low temperature, if necessary with cooling, as well as at room temperature or at elevated temperature, for instance at a temperature between about 30 C. and about 150 C., and preferably at the boiling point of the solvent employed. The quaternary ammonium compound can also be produced in a sealed tube.

The basic esters according to the present invention, their acid addition salts, and their quaternary ammonium compounds possess valuable therapeutic properties. They are highly effective spasmolytic agents having a neurotropically as well as a musculotropically effective component.

The following examples will serve to illustrate the present invention Without, however, limiting the same thereto.

Example 1 A Grignard solution prepared from 176' gm. of 2,5- endomethylene-A -cyclohexenyl bromide and 243 gm. magnesium metal in 400 cc. anhydrous ether was added dropwise, while cooling, to'a solution of 143 gm. benzoyl formic acid ethyl ester in 200 cc. anhydrous other within the course of 2 hours. The reaction mixture was stirred at room temperature for 7 hours and was subsequently heated to boiling for a-short period of time. After cooling, the reaction mixture was poured on a mixture of 7-50 gm. ice and 100 cc. 35% hydrochloric acid. Said mixture was then extracted with ether. The ethereal solution was dried over anhydrous sodium sulfate, the ether was evaporated, and the residue was subjected to fractional distillation in a high vacuum. 154 gm. a-(2,5-

endomethylene A cyclohexenyl) maudelic acid-ethyl I ester, having a boiling point of 135442 C./0.11 mun, were obtained.

Said ester was boiled under reflux with 1500 cc. of 60% methanol containing 110 gm. of potassium carbonate for 4 hours. tilled off until the residuein the distillation flask amounted toe volumeof about 800 cc. Said residue was acidified.

Subsequently, the methanol was dis-= by the addition of 17% hydrochloric acid. The precipitated oil was dissolved in ether. The ether was distilled off and the resulting oil was dissolved in 2 N potassium carbonate solution, again extracted with ether, acidified with 7% hydrochloric acid, and extracted with benzene. The benzene solution was subjected to distillation until all the water present therein was removed by azeotropic distillation. 9 parts of petroleum ether were added to the resulting residue and the mixture was allowed to stand at 0 C. for 2 days. 133 gm. (lb-(2,5- endomethylene-A cyclohexenyl)mandelic acid of the melting point 94 C. were obtained thereby.

By using, in place of benzoyl formic acid ethyl ester, equimolecular amounts of the following a-keto acid esters as starting materials, reacting said esters with the Grignard solution of 2,5-endomethylene-A -cyclohexenyl magnesium bromide or 2,5-endomethylene d -cyclohexenyl-magnesium chloride and otherwise following the procedure described hereinabove in Example 1, the following endocyclically substituted mandelic acid ethyl esters and the free acids derived therefrom, as shown in Examples 2 to 5 below, were obtained with a yield between about40% and about 70%.

Example 2 pvMethyl benzoyl formic acid ethyl ester yielded (2,5 endomethylene-A -cyclohexenyl)-p-methyl mandelic acid having a melting point of 102 C., and its ethyl ester having a boiling point of 165-169 C./25 mm. Hg.

Example 3 p-Isopropyl benzoyl formic acid ethyl ester yielded a-(2,5-endomethylene-A -cyclohexenyl)-p-isopropyl mandelic acid having a melting point of 132 C., and its ethyl ester having a boiling point of 1381'40 C./ 0.4 mm. Hg.

Example ,4

p-(n-Butoxyj-benzoyl formic acid ethyl ester yielded 0: (2,5 endomethylene-A -cyclohexenyl)-p-(n-butoxy)- mandelic acid having a melting point of C., and its ethyl ester having a melting point of 63 C.

Example 5 A Grignard solution prepared from 104 gm. of 2,5- endomethylene-M-cyclohexenyl bromide and 14.6 gm. of magnesium metal in 250cc. of anhydrous ether was added dropwise to -a solution of 30 gm. phenyl glyoxylic acid in 300 cc. anhydrous ether, which solution was previously cooled to --15 C. Thereafter the reaction mixture was stirred at room temperature for 1 hour, boiled under reflux for 2 hours, and cooled. The resulting granular precipitate was filtered 01f, washed with ether, decomposed with 300 cc. dilute 20% sulfuric acid, and extracted with ether. The resulting decomposition mixture was Worked up by following the procedure described in Example 1 and yielded a-(2,5-endomethylene-d -cyclohexenyD-mandelic acid as obtained according to said Example 1. The yield amounted to 62% of the theoretical yield.

Example 7 .By using, .in place of 2,5-endomethylenerA ecyclohexenyl bromide, the equimolecular amount of 2,5-endomethylene-cyclohexyl bromide but otherwise following the I were heated under reflux for 12 hours.

filtered while still hot.

5 gm. a-(2,5-endomethylene-A -cyclohexenyl)-mandelic acid prepared according to Example 1, 2.2 gm. fi-dimethylamino propyl chloride, and 60 cc. isopropanol The solution was The filtrate was concentrated by evaporation in a vacuum to a volume of 20 cc., cooled, and triturated with ether. 5.9 gm. a-(2,S-endomethylene- A -cyclohexenyl)-mandelic acid-p-dimethylarnino propyl ester hydrochloride, which after recrystallization from methyl-ethyl-ketone had a melting point of 165 C., were obtained.

By following the procedure described in Example 8 while replacing the S-dimethylamino propyl chloride with equimolecular amounts of amino alkyl halides, as indicated in Examples 9 to 14 below, and by replacing the tar-(2,5 endomethylene A -cyclohexenyl) mandelic acid with equimolecular amounts of endocyclically-substituted mandelic acids, as indicated in Examples 9 to 14 below, the corresponding basically substituted mandelic acid ester compounds were obtained.

Example 9 a-(2,S-endomethylene-cyclohexyl)-mandelic acid prepared according to Example 7 and p-dimethylamino ethyl chloride yielded a-(2,5-endomethylene-cyclohexyl)-mandelic acid-fl-dimethylamino-ethyl ester hydrochloride. Melting point after recrystallization from methyl-ethylketone: 161 C. Yield: 68% of the theoretical yield.

Example 10 a-(2,5-endomethylene-A -cyclohexenyl)-p-methyl mandelic acid, prepared according to Example 2, and fl-(4- morpholino)-ethyl chloride yielded a-(2,5-endomethylene- A cyclohexenyl) p methyl-mandelic acid ,B-(4 morpholino)-ethyl ester hydrochloride. Melting point after recrystallization from a mixture of isopropanol and ether (1:2): 176 C. Yield: 74% of the theoretical yield.

Example 11 Example 12 a (2,5-endomethylene-A -cyclohexeny)-3,4 dimethoxymandelic acid, prepared according to Example 5, and ,8- diethylamino ethyl chloride yielded a-(2,5-endomethylene- A -cyclohexenyl)-3,4-dimethoxy-mandelic acid-p-diethylamino-ethyl ester hydrochloride. Melting point after recrystallization from isopropanol: 117 C. The compound is highly hygroscopic.

Y Example 13 'a (2,5-endomethylene-A -cyclohexenyl)-mandelic acid, prepared according to Example 1, and B-(1-piperidino)- ethyl chloride yielded a-(2,5-endomethylene-A -cyclohexenyl)-rnandelic acid-p41-piperidino)-ethyl ester hydrochloride. Melting point after recrystallization from acetone: 180 Yieldi 68% of the theoretical yield.

-' Example 14 a:(2,5-endomethylene-A -cyclohexenyl)-p-methyl mandelic acid, prepared according to Example 2, and B-diethyl-amino ethyl chloride yielded a-(2,5-endomethylene- A cyclohexenyl)-p-methyl-mandelic acid-p-diethylamino ethyl ester hydrochloride. Melting point after recrystallization from a mixture of acetone and ether (1:2): 166

0'. Yield: 78% of the theoretical yield.

, 6 Example 15 5 gm. a-(2,S-endomethylene-A -cyclohexenyl)-p-(nbutoxy) -mandelic acid, prepared according to Example 4, 2.3 gm. ii-diethylamino ethyl chloride, and 60 cc. of ism propanol were heated under reflux for 12 hours. The resulting solution was filtered while still hot. Isopropanol was removed from the filtrate by vacuum distillation. The residue was dissolved in a small amount of water. Saturated potassium carbonate solution was added thereto and the mixture was extracted with ether. The ethereal extract was dried over anhydrous sodium sulfate and the ether was evaporated. The remaining basic ester was dissolved in 5 cc. isopropanol. The equimolecular amount of an 0.875 molar citric acid solution in ism propanol (18 cc.) was added thereto while heating. The resulting solution was allowed to stand at 0 C. for

several days, whereby the reaction product crystallized out. 6.8 gm. a-(2,5-endomethylene-M-cyclohexenyl)-p- (n-butoxy)-rnandeli c acid-fi-diethylamino ethyl ester citrate were obtained. Melting point after recrystallization from acetone: 68 C.

Example 16 3 gm. 18-(1-piperidino)-ethyl chloride dissolved in 10 cc. isopropanol were added dropwise to a boiling solution of 5 gm. a-(2,5-endornethylene-A -cyclohexenyl)-p-methyl-mandelic acid and 0.45 gm. sodium ill 60 cc. isopropanol within the course of one hour. The reaction mixture was boiled for additional 2 hours. The mixture was filtered while still hot. Isopropanol was removed from the filtrate by distillation in a vacuum. The residue was dissolved in ether. The ethereal solution was washed with saturated potassium carbonate solution and thereafter with water and was dried over anhydrous sodium sulfate. On treating said solution with dry gaseous hydrogen chloride, 5.9 gm. a-(2,5-endomethylene-A -cyclohexenyl)-pmethyl-mandelic acid-[H1-piperidino)-ethyl ester hydrochloride were obtained. Melting point after recrystallization from a mixture of isopropanol and ether (1:2): 157 C.

Example 17 27 gm. a-(2,S-endomethylene-A -cyclohexenyl)-mandelic acid-ethyl ester, prepared according to Example 1, were heated with 25 gm. diethylamino ethanol and about 0.05 gm. sodium in an oil bath to a temperature of C. until the ethanol set free during said esterification reaction was distilled off through a column of a length of 20 cm. and a diameter of 1 cm. 6 to 8 hours were required to complete the reaction. The residue was freed from excess diethylamino ethanol by heating in a vacuum and was dissolved in 2 N hydrochloric acid. The solution was washed with ether and was rendered alkaline by the addition of saturated potassium carbonate solution. The precipitated oil was dissolved in ether. The ethereal solution was dried over anhydrous sodium sulfate and was treated with an ethereal hydrogen chloride solution. 27 gm. a-(2,5-endomethylene A cyclohexenyl) mandelic acid-fi-diethylamino ethyl ester hydrochloride were obtained. Melting point after recrystallization from acetone: 163 C.

Example 18 Following the procedure described in Example 17 but using, in place of diethylamino ethanol, an equimolecular amount of dimethylamino ethanol as the one reaction component, yielded the corresponding a-(2,5-endomethylene-A -cyclohexenyl)-mandelic acid B dimethylamino ethyl ester hydrochloride. Melting point after recrystallization from acetone: 184 C. I

Example 19 4 gm. a-(2,5-endomethylene-A -cyclohexenyl)-mandelic acid-p-diethylamino-ethyl ester hydrochloride, prepared according to Example 17, were converted into the free base. Twice the required-amount of methyl bromide was '7 added to and admixed with said free base at a temperature of -40 C. The mixture was allowed to stand for 2hours at said temperature and was then kept at C.

overnight. The resulting precipitate was filtered 0E by suction, washed with ether, and recrystallized from acetone. 3.6 gm. a-(2,S-endomethylene-A ecyclohexenyl)- mandelic .acid-B-diethylamino-ethyl ester bromomethylate Were obtained. Melting point: 141 C.

I Example 20 4 gm. a-(2,5-endomethylene-A -cyclohexenyl') mande'lic acid- -dimethylamino-ethyl ester hydrochloride, prepared according to Example 18, were converted into the free base. Twice the required amount of methyl bromide was added and admixed with said free base, and the mixture was reacted and worked up as described in Example 19. 3.9 gm. a-(LS-endOmethyIene A cyclohexeny1)- mandelic acid-n-diethylamino-ethyl ester bromomethylate were'obtained. Melting point after recrystallization from ,iSQPITOPaHOII 170 C. Yield: 82% of the theoretical yield.

Example 21 I by vacuum distillation. The residue was dissolved in 2 N hydrochloric acid and the solution was extracted with other. A saturated potassium carbonate solution was then added and the resulting mixture was again extracted with ether. The latter ethereal extraction solution was dried over anhydroussodiurn sulfate and the ether was then evaporated, The remaining basic ester was converted into the corresponding hydrochloride by passing dry hydrogen chloride into an anhydrous ethereal solution of the base. Recrystallization of the reaction product from amixture of methyl-ethyl-ketone and isopropanol (10:1) yielded 32 gm. a-(2,5-endomethylene-A -cyclo hexenyl)- mandelic acid-fi-pyrrolidinoethyl ester hydrochloride, which had a melting Point of 165 C.

Example By reacting a-(2,5-endomethylene-A -cyclohexenyl)spmethyl-mandelicacid, prepared in accordance with Example 2 a e, with"fl-py rolid c yl hlorid i a manner analogous to that described In Exam le 24, 42,5-

endomethylene-A -cyc1ohexenyl)-p methyl-mandelic acid- (2,5-endomethylene-M-cyclohexenyl)-mandelic acid B-dimethylaminoethylester brornobutylate was obtained. Meltingpoint: 198 C.

Example 22 1 gm. a-(2,5aendomethylene-A -cyclohexenyl') -mandelic acid-B-dimethylaminoethylester' hydrochloride, prepared acid-B-dimethylaminoethylester decylobromate were ob-.

tained. Melting point: 293 C.

Example '23 3.2 gm. a-(2,5:endomethylene-d -cyclohexenyl).-mandelic acid-,B-dimethylamino-ethyl ,esterhydrochloride,prepared in accordance with Example '18 above, were ,converted into the free base. Twice the required amount of benzylbromide was added thereto, and the mixture was then maintained at 130 C. for about half an hour. After cooling, the excess benzylbromide was removed from the reaction mass by distillation in vacuo. .The residue was admixed with ether, the mixture was filtered, the filter cake was Washed withflether and recrystallized from a mixture of acetone and ether (2:1). 3.5 gm. a-(2,5-end0rnethyiene-A -cyciohcxcnyl)-mandelic acid-B dimethylamino-ethyl ester benzylobrornate were obtained, which had ameltingpoint of 168 C.

Example 24 29:5 gm. a-(2,S-endornethylene+A scyclohexeuyl) man delie acid, prepared in accordance with Example 1. above,

were admixed with 16.2 gm. pyrrolidinoethylchloride, 42.9 gm. potassium carbonate and 350 cc.ethyl acetate, and the mixture was heated under .refiuxfor about 24 hours. Thereafter, the reaction mixture was filtered while still hot. EEx-cess ethyl acetatewas, removed frcmthe, filtrate B-pyrrolidinoethyl ester hydrochloride was obtained. The melting point of this compound, after recrystallization from a mixture of methyl-ethyl-ketone and isopropanol 10:1), was 174- C. The yield was 90% of theory.

Example 26 9 gm. u-(2,5 endomethylene-M-cyclohexenyl)-mandelic acid-fl-pyrrolidinoethyl ester hydrochloride, prepared in accordance .With Example 24 above, were converted into the corresponding free base. Twice the required amount of methylbromide and 100 cc. ethyl acetate were added to the free base While maintaining the mixture at -20 C.; thereafter, thereactionmixture was maintained at about 0 C. for .48 hours. The reaction product was filtered off, washed with ether and rec ystallized from a mixture of methyl-.ethyl-ketone and isopropanol (10: 1). ot- (2,5 endornethylene-A -cyclohexenyl -mandelic acid-fl-pyrrolidinoethyl ester methylobromate, haying a melting point of 171 C., was obtained with a yield corresponding to 78% of theory.

Example 27 13.8 gm. 0: 2,5-endomethylene-M-cyclohexenyl) pmethyl-mandelic acid-fi-pyrrolidinoethyl ester, prepared in accordance with Example '25 above, were converted into the correspondingfr ee base. Twice the required amount of methylbromide and 100 cc. ethyl acetate were added to the free base while maintaining the mixture at -20 C.; thereafter, the reaction'mixture was maintained at 0 C. for about 48 hours. The reaction product was filtered ofi, washed with ether and recrystallized from a mixture of methyl-ethylketone and isopropanol (10:1). u-(2,S-endomethylene-A -cyclohexenyl) p methyl-mandel-ic acid-fi-pyrrolidinoethyl ester methylobromate, having a melting point of 208 C, was obtained with ;a yield corresponding --to 93% of "theory.

As stated above, the new basic esters and especially their acid addition salts and quaternary ammonium compounds are excellent spasmolytic agents. They canbe activity similar to ;that.of-papaverine. .Such compounds are, for instance, a:(2,S-endomethylene-A rcyclohexenyl).-

p-isopropyl-mandelic. acid- 3 d iethylamino-ethylester :hy-

' drochloride and oz-(2,S-endomethylene-A -cyclohexenyl)- p-methyl-mandelic acid d-piperidinoethylester hydrochlo" ride.

Qther compounds produced according to the present invention exhibit a highuneurotropic activity, i.e. .an ,activity similar to that of atropine. v,Such compounds are, for instance: a-(2,5-endomethylene-A cyclohexen yl)- mandelic acid- :dimethylaminoethylester hydrochloride; a-(2,5-endomethylene A3 eyclghexenyD:mandelic add-e Maximum dose Activity of compounds Orally, gm. Parenterally,

(1) Papavcrine-like (2) Atropine-like (3) Papaverineand atropine-like 0.

The new basic esters, their acid addition salts, and their quaternary ammonium compounds are therapeutically administered for abolishing spasms of the smooth muscles. For instance, visceral and uterine spasms, vesical spasms, spasms of the ureter, the bile duct and the gall bladder, and spasms during labor may be relieved by said drugs. They have also proved of value in the treatment of spastic conditions associated with dysmenorrhea, stomach and intestinal ulcers, hyperacidity, asthmatic conditions, vegetative dystonia. They are useful in oph thalmology for diagnostic and therapeutic purposes; for instance, as mydriatics prior to retinoscopy.

It is to be understood that many changes and variations in the reaction components, the reaction conditions, the temperature, duration of the reaction, and the solvents used, the methods of working up the reaction mixture and of isolating and purifying the reaction products, and the like, may be made by persons skilled in the art in accordance with the principles set forth herein and within the scope of the claims annexed hereto.

10 We claim: 1. Endocyclically-substituted mandelic acid basic ester compounds having a structural formula selected from the group consisting of wherein R is selected from the group consisting of hydrogen, alkyl with 1 to 6 carbon atoms and alkoxy with 1 to 4 carbon atoms, R is selected from the group consisting of hydrogen and alkoxy with 1 to 2 carbon atoms, E is selected from the group consisting of 2,5-endomethylene-A -cyclohexenyl and 2,5-endomethylene-cyclo hexyl, R and R are selected from the group consisting of alkyl with 1 to 4 carbon atoms and, together with the nitrogen atom, a heterocyclic chain selected from the group consisting of pipe-ridino, pyrrolidino and morpholino, X is alkylene with 1 to 4 carbon atoms, R is selected from the group consisting of hydrogen, aralkyl and :alkyl with 1 to 10 carbon atoms, and Y is an anion selected from the group consisting of therapeutically useful anions of inorganic and organic acids.

2. a-(2,S-endornethylene-A cyclohexenyl) mandelic acid-fl-dimethylamino-ethyl ester.

3. x-(2,5-endomethylene-A cyclohexenyl) mandelic acid-[B-diethylamino-ethyl ester.

4. u-(2,5 endomethylene-A -cyclohexenyl)-p-methylnrandelic acid-fl-diethylamino-ethyl ester.

5. The a-(2,5-endomethylene-A -cyclohexenyl) -mandelic acid-B-dimethylamino-ethyl ester bromomethylate.

6. The w(2,5-endomethylene-A -cyclohexenyl) mandelic-acid-,H-pyrrolidino-ethylester-bromomethylate.

References Cited in the file of this patent UNITED STATES PATENTS 2,265,184 Miescher et a1. Dec. 9, 1941 2,490,964 Hoffman et a1. Dec. 13, 1949 2,789,110 Klavehn Apr. 16, 1957 

1. ENDOCYCLICALLY-SUBSTITUTED MANDELIC ACID BASIC ESTER COMPOUNDS HAVING A STRUCTURAL FORMULA SELECTED FROM THE GROUP CONSISTING OF
 6. THE A-(2,5-ENDOMETHYLENE-$3-CYCLOHEXENYL) - MANDELIC-ACID-B-PYRROLIDINO-ETHYLESTER-BROMOMETHYLATE. 